The human multi-drug resistance (MDR1) gene makes a protein called P-glycoprotein (P-gp). P-gp may limit the absorption of medications including HIV protease inhibitors. HIV protease inhibitors are drugs used to treat people with HIV infection (the virus that casues AIDS). It is possible that the particular type of MDR1 gene that a person possesses (their genotype) influences the extent that P-gp limits the absorption of HIV protease inhibitors. The purpose of this study is to see how the MDR1 genes that each person got from his or her parents might affect how well he or she absorbs the protease inhibitors indinavir and saquinavir. This study will screen 150 healthy volunteers to determine their MDR1 genotype; 60 of these volunteers will receive saquinavir (10 doses) and indinavir (4 doses) and blood will be collected afterward to see whether MDR1 genotype influneces the blood levels of these HIV medicines. Study subjects will also receive a single dose of midazolam to measure the activity of a particular enzyme (CYP3A) that is involved in breaking down saquinavir and indinavir in the body. To date, 38 subjects have completed the investigation; 53% of whom expressed the C3435T genotype, 26% the CC genotype, and 21% the TT genotype. Percentages were similar for G2677T, GG, and TT genotypes. The average saquinavir maximum concentration (Cmax) was significantly higher among TT subjects vs. GG subjects (1220 vs. 776 ng/mL; P=.05) at position 2677. Average saquinavir AUC values over 0-2, 0-4, and 0-8 hrs were TT>CT>CC and TT>GT>GG at positions 3435 and 2677, respectively; however, these differences were not statistically significant in this preliminary analysis (P > .05). Saquinavir elimination (T ?) and apparent oral clearance (Cl/F) were comparable between all groups (P=NS). These preliminary findings suggest that saquinavir absorption may be enhanced in TT vs. CC and TT vs. GG individuals at positions 3435 and 2677, respectively. As such, these data suggest that MDR1 genotype may influence saquinavir exposure. Further study will determine the importance of these findings in HIV-infected patients. Of note, MDR1 genotype did not appear to influence indinavir pharmacokientics nor did midazolam predict saquinavir or indinavir pharmacokinetic parameter values. Results from this investigation also revealed a lack of sex-related differences in saquinavir pharmacokinetics, which is inconsistent with previous reports. Thirty-eight healthy volunteers (14 female) received saquinavir soft-gel capsules 1200 mg three times daily for 3 days to achieve steady state conditions. Following administration of the 10th dose, blood was collected serially over 8 hours for measurement of saquinavir plasma concentrations. Saquinavir pharmacokinetic parameter values were determined using non-compartmental methods and compared between males and females. CYP3A phenotype (using oral midazolam) and MDR-1 genotypes at positions 3435 and 2677 were determined for all subjects in order to characterize possible mechanisms for any observed sex-related differences. There was no significant difference in saquinavir AUC0-8 or any other pharmacokinetic parameter value between the sexes. These findings persisted after mathematically correcting for total body weight. The mean weight-normalized AUC0-8 was 29.9 (95% CI 15.5 ? 44.3) and 29.8 (18.6 ? 40.9) ng?hr/ml/kg for males and females, respectively. No significant difference in CYP3A phenotype was observed between the groups; likewise, the distribution of MDR-1 genotypes was similar for males and females.In contrast to previous study findings, results from this investigation showed no difference in saquinavir pharmacokinetics between males and females. The discrepancy between our findings and those previously reported may be explained by the fact that we evaluated HIV-seronegative volunteers and administered saquinavir in the absence of concomitant protease inhibitors such as ritonavir. Caution must be exercised when extrapolating pharmacokinetic data from healthy volunteer studies (including sex-based pharmacokinetic differences) to HIV-infected populations or to patients receiving additional concurrent medications.